N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury

Modulation of N-acylethanolamine-hydrolyzing acid amidase (NAAA) represents a potential alternative strategy in the treatment of neuroinflammation. Recent studies showed that pharmacological modulation of NAAA could be achieved with the oxazoline of palmitoylethanolamide (PEA; PEA-OXA). The aim of this study was to evaluate the neuroprotective effects of PEA-OXA in the secondary neuroinflammatory events induced by spinai and brain trauma in mice. Animals were subjected to spinai cord and brain injury rnodels and PEA-OXA (IO mg/kg) was adrninistered both intraperitoneally and orally l h and 6 h after trauma. PEA-OXA treatment markedly reduced the histological alterations induced by spinai cord injury (SCI) and traumatic brain injury (TBI) and ameliorated the motor function and behavioral deficits, as well. In addition, the expression of neurotrophic factors, such as glial celi line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophin-3 were increased by PEA-OXA treatment. Moreover, PEA-OXA also significantly decreased glia! fibrillary acidic protein hyperexpression, the nuclear translocation of nuclear factor (NF)-ĸB, phosphorylation of Ser536 on the NF-ĸB subunit p65, and degradation of IĸB-ɑ, as well as diminished the expression of proinflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, tumor necrosis factor (TNF)-ɑ and interleukin (IL)-1β. The rnodulation of intracellular NAAA by PEA-OXA treatment could thus represent a novel therapy to contro] neuroinflarnrnatory conditions associated with SCI and TBI.